Amino acid derivatives by asymmetric

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

Synthesis of Unnatural Amino Acid Derivatives by Asymmetric Alkylation... 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

An alternative approach to 1,4-addition affording / -amino acid derivatives, by use of Lewis acid-hydroxyamine hybrid reagents (LHHR), was also investigated [122]. LHHR were ten times more reactive than benzylhydroxyamine itself. This reagent-controlled asymmetric 1,4-addition using aluniinum-hydroxyamine complexes resulted in moderate enantioselectivity (43-71% ee) (Scheme 6.98). 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

The addition of cyanide to imines forms the basis of the Strecker reaction, and can be used in the synthesis of amino acid derivatives by hydrolysis of the nitrile to the acid. The asymmetric variant of this reaction can be achieved using both metal-based catalysts and organocatalysts. ... 

Parallel to the above approach efficient synthesis of P-amino acid derivatives by the use of Sn(II) enolates and a-aminoesters have been carried out by Japanese workers [90]. The most recent asymmetric synthesis of a (-h)-6-epi PS-5 carbapenem building block through this methodology (Scheme 33), involved... 

Bamish FT, Corless M, Dunn PJ, Ellis D, Finn PW, Hard-stone JD, James K. Asymmetric synthesis of -amino acid derivatives by Michael addition to chiral 2-aminomethyla-crylates. Tetrahedron Lett. 1993 34 1323 1326. 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

By using a mixture of ethyl acetate and D2O as solvent for hydrogenation, up to 75% deuterium is incorporated in the reduced product.13 This result indicates that the role of water here is not only as a solvent. Research on asymmetric hydrogenation in an aqueous medium is still actively being pursued. The method has been applied extensively in the synthesis of various amino acid derivatives.14... 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

Scheme 10. Asymmetric synthesis of the a,a-dialkyl-a-amino acids 37 by use of the cinchona alkaloid derivative 12.

A fi-keto-bis-a-amino acid derivative 267 is a common precursor in these syntheses (Scheme 57), obtained by asymmetric Schollkopf alkylation <1994TL4091>, by Claisen condensation of glutamic acid precursors <1997TL6483, 1998JOC5937>, or by hydrogenation of bis-a,/3-unsaturated amino acid derivatives <2001TL3159>. 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

The bacteriostatic gliotoxin was prepared206 by a total synthesis involving an asymmetric Michael-addition. A chiral amino acid derivative served as chiral auxiliary in the key step. 

Mur 207), has received renewed interest in recent years. A fine review covering the intermolecular asymmetric Diels-Alder reaction was compiled by Mori 208>. In this article the use of terpenes and carbohydrates as chiral auxiliaries is discussed no amino acid derivatives are mentioned in this context. A chiral a-hydroxycarboxylic acid derivative was also used to achieve an asymmetric Diels-Alder reaction 209). High asymmetric induction could be detected in the intramolecular Diels-Alder reaction of chiral molecules. 

Even in such molecules with large ground state dipole moment, we observed the production of non-centrosymmetric crystal structures exhibiting SHG by introduction of asymmetric amino acid derivatives into the cyclobutenedione. (-)4-(4,-dimethylaminophenyl)-3-(2l-hydroxypropylamino) cyclobutene-1,2-dione (DAD) (3), (+)4-(4 -di-... 

It is also important to note that the potential synthetic utility of the asymmetric alkylation protocol discussed in this section has been fruitfully demonstrated by its application to the stereoselective synthesis of various biologically adive natural products possessing unique a-amino acid derivatives as their structural components [27,28]. 

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